Novel chromone derivatives and the production thereof

ABSTRACT

Chromones of the formula are disclosed   WHEREIN M IS 0, 1 OR 2 AND R1 is halo, hydroxy, nitro, amino, lower alkylamino, lower alkyl, lower alkoxy, or lower acyloxy. These compounds are useful as anti-allergy agents.

[j iie gags Ukyo et al.

aieni 1 1 Mar. 18, 1975 NOVEL CHROMONE DERIVATIVES AND THE PRODUCTION THEREOF [75] Inventors: Akira Nohara Ukyo; Tomonobu Umetani; Yoshibumi Miyata; Yasushi Sanno, all of Osaka, Japan [73] Assignee: Takeda Chemical Industries, Ltd.,

Osaka, Japan [22] Filed: Nov. 1, 1972 [21] Appl. No.: 302,652

[30] Foreign Application Priority Data Nov. 4, l97l Japan 46-87880 [52] U.S. Cl 260/345.2, 424/283, 260/345.5 [5 1] Int. Cl C07d 7/52 [58] Field of Search 260/3452, 345.5

[56] References Cited OTHER PUBLICATIONS Boehm et al., Chemical Abstracts, Vol. 28, Cols. 1033 to l()34 (I934).

Checchi et al., 62122. Chim. Ital. Vol. 95. pages 1502 to 1512 (1965) Primary Examiner-John D. Randolph wherein m is O, I or 2 and R is halo, hydroxy, nitro, amino, lower alkylamino, lower alkyl, lower alkoxy, or lower acyloxy. These compounds are useful as antiallergy agents.

28 Claims, N0 Drawings NOVEL CHROMONE DERIVATIVES AND THE PRODUCTION THEREOF The present invention relates to novel chromone derivatives and their pharmaceutically acceptable salts, which have effective anti-allergic action, as well as to a process for the production of these compounds.

There have been employed many kinds of antihistaminic agents or bronchodilators for the treatment of bronchial asthma. However, the aforesaid antihistaminic agents show only antagonism towards histamine released or produced in a living body and thus they are not satisfactory in treating bronchial asthma. More specifically, they are not effective in the treatment of bronchial asthma which is caused by chemical mediators other than histamines. In respect to the aforesaid bronchodilators, they show only a direct dilating action on bronchial smooth muscle, and therefore they can be used only as a symptomatic drug.

On the other hand, it has recently been reported that an SRS-A(slow reacting substance of anaphylaxis) secreted from cells of a living body plays a very important part in the development of allergic phenomena including bronchial asthma and that inhibition of the secretion of SRS-A or the blocking action of SRS-A is very effective in the treatment of bronchial asthma.

Under these circumstances, the present inventors have made extensive studies to find out pharmaceuticals effective in inhibiting the secretion of SRS-A or blocking the action of SRS-A. As a result, they have succeeded in synthesizing novel chromone derivatives and establishing their pharmacological effects for the purposes intended, the aforesaid chromone derivatives being of the formula:

wherein m is 0, l or 2 and each of R is a halogen atom, hydroxy, nitro, amino, lower alkylamino, lower alkyl, lower alkoxy or a lower acyloxy group.

These compounds (I) strongly inhibit the secretion of SRS-A, histamine and other chemical mediators from cells ofliving body, and are characterized by low toxicity; furthermore they even exhibit the aforesaid activity upon oral administration.

Taking advantage of these characteristics, the present compounds (I) can be used as an effective medicine for preventing and/or treating allergic diseases, especially bronchial asthma, by means of oral administratron.

Thus, the principal object of the present invention is to provide novel chromone derivatives (l) and their pharmaceutically acceptable salts which are useful as effective anti-allergic agents. Another object is to provide a method for producing these compounds.

Referring to the formula (I), the halogen atom may be any of chlorine, bromine, iodine and fluorine. The lower alkyl group may be suitably one having up to six carbon atoms, which may be any of the straight, branched chain or cyclic type. Typical examples of the lower alkyl group are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopentyl and cyelohexyl. The lower alkoxy group may be suitably one having up to four carbon atoms. The lower alkoxy group includes methoxy, ethoxy, propoxy and butoxy groups.

The lower acyloxy group may be suitably one having up to seven carbon atoms, and exemplified by formyloxy, acetyloxy, propionyloxy, butyryloxy and benzoyloxy.

The lower alkylamino group may be a mono-lower alkylamino or di-lower alkylamino, the lower alkyl group being suitably one having up to four carbon atoms which includes methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino and dipropylamino groups.

In the formula (I), R may occupy any position in the 5-,6-,7- and the 8positions of the chromone ring when m is l, and the two substituents of R which are the same or different, may occupy optionally two positions in the 5-, 6-, 7- and 8-positions when m is 2.

The present compounds of the formula (I) may be produced by, for example, reacting a compound of the wherein m and R, are as defined above with a compound of the formula:

(III) wherein R and R may be the same or different, are cyano, carboxyl or a group derived from a carboxyl group.

Referring to the formula (Ill), the groups derived from the carboxyl group include esterfied carboxyl and carboxamide.

The esterified carboxyl group can be shown by the formula X OOC- (wherein X is a hydrocarbon residue). The hydrocarbon residue is suitably one having up to eight carbon atoms and may be any of a straight or branched chain, cyclic, saturated or unsaturated alkyl groups, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl and aralkyl groups such as benzyl and phenethyl.

The carboxamide group can be shown by the formula X OC (wherein X is an amino or a substituted amino group). The substituted amino group represented by the symbol X includes an alkylamino, dialkylamino, arylamino, aralkylamino, cyclic amino group, etc. Typical examples of such groups are methylamino, dimethylamino, diethylamino, 2- hydroxyethylamino, bis(2-hydroxyethyl)amino, benzylamino, phenylamino and morpholino.

In the preparation of the desired products (I), the starting compounds (III) are generally be employed in an amount of from about l to 2 mols relative to l mol of compounds (ll).

The reaction between a compound of the formula (II) and a compound of the formula (III) may suitably be carried out in the presence of a solvent in which case, the reaction is conducted in the presence of a basic reagent or an acid anhydride. Solvents which may be used for this purpose include hydrocarbons (e.g. benzene or toluene), alcohols (e.g. methanol or ethanol) or a mixture of such solvents. Basic reagents which may be used include tertiary amines such as trimethylamine, triethylamine, N-methylpiperazine, N- methylmorpholine, N-methylpyrrolidine and basic heteroaromatic compounds such as pyridine, quinoline, imidazole, Z-methylimidazole, etc. Acid anhydrides which may be used include formic anhydride, acetic anhydride, propionic anhydride, succinic anhy dride and benzoic anhydride. Among these basic reagent and acid anhydrides, the basic heteroaromatic compounds are most advantageous for practical purposes and can function as a reaction solvent as well.

While the reaction conditions including the temperature and time of the reaction depend upon such factors as the particular starting compound, the solvent and other factors, the reaction may be carried out at a temperature of from about 50 to about 160C, and most advantageously from about 100 to about 150C, for a period from several minutes to about hours.

By the said reaction between the compound of the formula (II) and the compound of the formula (III), the desired products (I) are directly produced when both R and R of the compound (III) are carboxyl, i.e., the compound (III) is malonic acid.

Where R is carboxyl and R is cyano or a group derived from carboxyl such as an esterified carboxyl or carboxamide, a compound of the formula:

wherein m and R are as defined above and R is cyano or the group derived from carboxyl, is formed by the said reaction.

When both R and R of the compound (III) are cyano or the group derived from a carboxyl group, a compound of the formula: v

O h 1 3 Ji 0H=0 2 rig 0 wherein m and R are as defined above and R and R which may be same or different, cyano or a group derived from carboxyl, is produced by the reaction between the compound (II) and the compound (III).

The thus formed compounds (IV) and (V) can be easily converted into the desired products (I) by hydrolyzing such starting compounds. The compound (IV) or (V) may be subjected to hydrolysis as it is, in the reaction mixture or after it is isolated from the reaction mixture by a conventional means such as extraction, chromatography or recrystallization.

In this hydrolysis step, one may employ any means in so far as it is capable of converting cyano or the group derived from the carboxyl to the free carboxylic acid except for those which will affect the benzopyran ring of the compounds (IV) or (V).

For example, the desired products of the formula (I) can be obtained by a reaction in which the compound (IV) or (V) is heated together with water and an inorganic acid such as sulfuric acid, hydrochloric acid or hydrobromic acid; or with water and an organic acid such as acetic acid; or with a mixture of inorganic and organic acids; or with water and an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. When R of the formula (IV) or R and/or R of the formula (V) are cyano groups, it is also possible that the compound (IV) or (V) is converted to the desired products (I) by treating the compound (IV) or (V) in the presence of a gaseous hydrogen halide such as hydrogen chloride or concentrated sulfuric acid and an alcohol such as methanol or ethanol to obtain the iminoester derivatives corresponding to the alcohol used and then, hydrolyzing the iminoester derivatives under the above-mentioned conditions.

When R of the thus-obtained product (I) is a lower alkoxy or a lower acyloxy group, one may convert said groups to a hydroxy group by any means commonly used in the cleavage of the ether linkage (e.g., hydrolysis by heating with a concentrated mineral acid such as concentrated hydrobromic acid or concentrated hydroiodic acid with or without a suitable solvent such as acetic acid) or by any means which is routinely used in the cleavage reaction of ester bonds (e.g. hydrolysis with a hydrohalogenic acid such as hydrochloric acid or hydrobromic acid or an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide).

Conversely, when R is hydroxy] group, it may be alkylated with a common alkylating agent (e.g. dimethyl sulfate) to form a lower alkoxy group corresponding to said alkylating agent.

In the method of the present invention, the desired products (I) are predominantly produced in the transform, and even if a small amount of the cis-form compound is produced, it can easily be separated from the trans-form compound, for example, by the conventional isolation procedures such as recrystallization from an organic solvent (e.g. acetone, dimethylformamide, methanol, ethanol) or chromatography (e.g. silicagel column chromatography). Throughout the present specification, the trans-indication concerns the acrylic acid moiety of the compound (I).

From the viewpoint of pharmaceutical activity such as anti-allergic action, the trans-form of the products (I) is superior to the cis-form of such compounds.

The thus produced products (I) can be converted to their corresponding alkali metal salts or ammonium salts by a per se conventional manner using a compound which can supply an alkali metal ion or an ammonium ion. Typical examples of such compounds may be an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide), alkali metal carbonate or alkali metal bicarbonate (e.g. sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate), alkali type strong cation exchange resins (e.g. sodium type of Amberlite IR-I20; manufactured by Rohm & Haas Co., U.S.A.) or ammonium hydroxide.

The compounds (I) can also be converted to their organic amine salts by reaction with a suitable organic amine. The typical examples of the organic amine to be used suitably in the present invention may be mono-, dior triethanolamine, diethylamine, triethylamine, dlmethylephedrine, l-(3,5-dihydroxyphenyl)-L-isopropyl-aminoethanol, isoproterenol( 3 ,4-dihydroxy-a- [(isopropyl-amino)methyl)benzyl alcohol),

hetrazan(diethylcarbamazine), dextromethorphan(d- 3-methoxy-N-methylmorphinan).

The thus produced products (I) or their salts may be easily separated from the reaction mixture and purified by a per se known means (e.g. extraction, distillation, recrystallization, chromatography).

The compounds (I) or their pharmaceutically acceptable salts have effective anti-allergic action and are useful as medicines in the treatment of allergic diseases such as hay fever, urticaria, allergic bronchial asthma, allergic rhinitis, dermatoses, and the like.

The following is an example of the tests in which the anti-allergic action of illustrative compounds of the present invention is demonstrated.

TEST FOR ANTI-ALLERGIC ACTION The following process for evaluation of the effect of a compound (I) which inhibits the release of the mediators on anaphylaxis initiated by passively sensitizing with skin sensitizing antibodies is applied.

In this test, the inhibiting effect of a compound (I) against passive cutaneous anaphylaxis in rats is evaluated.

First, serum for a passive cutaneous anaphylaxis (PCA) reaction, whose PCA titer is I116, is prepared in accordance with Motas method (Life Science 2, 9l7( 1963)), and diluted four times with physiological saline solution to obtain a diluent A.

In the second step, rats (Spregue Dawley-JCL, male body weight: about 250g.) are passively sensitized with an intradermal injection of 0.05 ml. of the diluent A of four points of the rats back skin, which has been clipped with electric clippers. Seventytwo hours after the sensitization, l ml. per rat of a solution containing 5 mg. of antigen (egg albumin) and I mg. of Evans blue in physiological saline solution is injected intravenously in each rat to challenge skin anaphylaxis.

Thirty minutes after the injection, all rats are decapitated. Then, the back skin is flayed and a dimension of dye leaked inside the skin is measured. The dimension of the dye leaked observed in this experiment of control rats ranges from 250 to 300 mm.

Each test compound is injected in 0.5 ml. volume of physiological saline solution per rat at various doses ranging from 0.6 mg./kg. to 5mg./kg. intravenously in three animals at each dose level just before challenging.

For the purpose of drug evaluation, the percentages of inhibition are calculated according to the following equation:

% Inhibition (l Mean value of dimension of dye leaked of administered group/Mean value of dimension of dye leaked of control group X I00 A 50 percentage inhibition dose of each compound is calculated from the dose response curve graphically.

The results are shown in the following table 1:

Continued 7 Trans 3-(6-methoxy-4-oxo-4H-l- Moreover, the salts of the products (I) have generally high solubility in water, and therefore, it is practically convenient to use the salts, especially the organic amine salts of compounds (I) as medicines from the pharmaceutical and pharmacological point of view.

When the compounds (I) or their pharmaceutically acceptable salts are employed as anti-allergic agents for treating or/and preventing allergic diseases such as bronchial asthma, dermatoses and rhinitis, these com pounds are administered in per se or in the form of a pharmaceutically acceptable composition in admixture with a suitable and conventional carriers or diluents.

The pharmaceutical composition may take the form of tablet, capsules granules, powders, solutions, injections, ointment, spray or inhalant, and may be adminis tered orally and parenterally.

The therapeutically active usual daily doses of the compounds of the present invention is in the range of from about I to about 500 mgs. when administered orally or intravenously in an adult human.

The starting compounds (II) of the present invention may be produced, for example, by the processes illustrated by the following schema:

Vilsmeier 3 reagent:

wherein m and R, are as defined above.

This reaction is conducted by reacting a compound of the formula (VI) with the Vilsmeier reagent which consists of equivalent mol(s) of dimethylformamide and an acid chloride such as phosphorus oxychloride, tetrachloropyrophosphate, thionyl chloride, phosgene, phosphorus pcntachloride, etc., in the presence or absence of a suitable solvent. As the solvent, any solvent which does not hinder the reaction may be employed. Typical examples of such solvents are dimethylformamide, benzene, chloroform, or mixtures thereof.

The amount of dimethylformamide and acid chloride used is generally at least not less than about 2 mols, more suitably about 2 to 6 mols per mol ofa compound of the formula (VI), respectively. The reaction can proceed at room temperature under atmospheric pressure, but, if necessary, may becarried out under heating up to about C or cooling to about 20C, or under elevated pressure. The reaction time varies with reaction conditions such as temperature, pressure or the type of acid chloride and solvent used, but it is generally about 1 to 24 hours.

For further explanation of the present invention, the following Reference and Examples are given, wherein the word part(s)" is based on weight unless otherwise noted and the relationship between part(s)" and part(s) by volume corresponds to that between milligrams(s) and milliliter(s); and throughout the specification the abbreviation mg, kg., ml.," C, N, mm." and Hz." refer to milligram(s)," gram(s), kilogram(s), milliliter(s), degree(s) Centigrade, Normal(s)," millimeter(s) and Hertz, respectively.

REFERENCE Calculated for C H O C, 62.07; H, 3.47 Found: C, 62.12; H, 3.43

The following compounds are prepared by a similar manner to the procedure set forth above.

in parts by volume of pyridine is heated in an oil bath, temperature of which is at 110C, for 1 hour, after which time an additional 500 parts of dry malonic acid is added. The mixture is then heated at l 10C for an additional minutes. The reaction mixture is concentrated and 20 parts by volume of acetone is added to the residual crystals which are then collected by filtration. The filtrate is concentrated and 20 parts by volume of acetone is added to the residue. Then, the solid product is collected by filtration and combined with the crystals previously obtained. These crystals are dissolved in 500 parts by volume of acetone while heating, decolorized with activated carbon and filtered while heating. The filtrate is allowed to stand in a refrigerator for 3 hours to obtain crystals. The procedure yields 3,200 parts of trans 3-(4-oxo-4H-l-benzopyran 3)acry1ic acid as pale yellowish needles melting at Further, the above-obtained 7-acetoxy-4-oxo-4H-lbenzopyran-3-carboxaldehyde is hydrolyzed with concentrated'hydrochloric acid and acetic acid to obtain 7-hyd roxy-4-ox0-4H- 1 -benzophran-3-carboxaldehyde melting point 265.5268.5C(decomposition), in the form of yellow prisms recrystallized from dimethylformamide acetone water) which is then methylated Qwith dimethyl sulfate to obtain 7-meth0xy-4-oxo-4H-1- benzo-pyran-3-earboxaldehyde (melting point l88-189C, in the form of pale yellowish needles recrystallized from acetone).

EXAMPLE 1 A solution of 3,480 parts of 4-oxo-4H- lv-benzopyran- 245246C(decomposition with foaming). Elemental analysis Calculated for C I-1,0 C, 66.67; H, 3.73 Found: C, 66.61; H, 3.56

Nuclear Magnetic Resonance spectrum (d -dimethylsulfoxide)d: 8.82(1H, singlet, H about 8.12(1H,quartet,H 7.9 7.4(3H, aromatic), 7.10( l H,doublet,J=l6Hz.,H 7.4l( l H,doublet,J=16Hz.,H

Mass spectrum m/e 2l6(M 171 EXAMPLES 2-16 The following compounds are synthesized by proce- 3-carboxaldehyde and 2,080 parts of dry malonic acid dures similar to the procedure described in Example 1.

Exam 10 Crystal Meltlng p Starting compounds Product form point Solvent Ior recrystallization 7-AcetoXy4oXo4Hl- Trans 5-(7- Light 288-290 benzopyran-3- hydroxy-4- yellowish/ (decompo- 2 carboxaldehyde oXo lHlsolid 51 12101].

benzopyranwltn 3 liicry 11C Dimethyl foamlng l Malonlc acld aeld formamide water A C ontinucd Wu" D Crystal Melting Exampl Starting compounds Product 130M point N-O o 0C) Solvent for recrystal- "'1 lization 5-Acetoxy-4-oXo-4H-l- Trans 3-(5- Light 284-285 benzopyran-3- hydroXylyellow (decompo- 3 carboxaldehyde oXo-4H-lneedles sition benzopyranwith 3)acrylic Dimethyl foaming) n I I M lonic acid acid formamide water 7-HydroXy-4-oxo-4H-l- Trans 5-(7- Light 288-290 benzopyran-3- hydroxy-4- yellow (decompo- 4 carboxaldehyde oXo-4H-lsolid sition benzopyranwith 3)acrylic foaming lmetnyl- Malonlc acid acid formamide,

v water 7-I'IethoXy-4-oXo-4H-l- Trans 5-(7- Light 265-266 benzopyran-3- methoXyryellow (decompo- 5 1 carboxaldehyde OXO-4H-lneedles sition benzopyranwith 3)acrylic foaming I D1methyl- Melanie acid acid formamide 9 acetone 6,7-Diacetoxy-4-oxo- Trans 3-(6, Yellow 246-247 4H-l-benzopyran-3- 7-diacetoxysolid (decompo- 6 carboxaldehyde 4-oXo-4H-lsition benzopyranwith 5): crylic gitfiggig foaming) Malonic acid acid Water 6,7-Dihydroxy-4-oxo- Trans 5-(46, Yellow 4H-l-benzopyran-3- 7-dihydroxyneedles 300 or 7 carboxaldehyde 4-oXo-4H-lhigher benzopyran- 5)acrylic Malonic acid acid 6,8-Dimethyl-4-oxo- Trans 5-(6, Colorless 286-288 4H-l-benzopyran-3- 8-dimethylfine decomposi- 8 carboxaldehyde 4-oxo-4H-lneedles tion) benzopyran- 5)acrylic Malonic acid acid 01311116131371 :ormamide,

ethanol Continued Exa Crystal Melting 23 Starting compounds Product V point Solvent 1 for l I recrystalilization 6,8--Dibromo4-oXo-- Trans 5-(6, Pale 275- 77 4H-l-benzopyran-3- 8-dibromoyellow (decomposi- 9 carboxaldehyde 4-oXo4H-l needles tion) benzopyran- I acrylic: Dimethyl- Malonic acid acid formamide 6-N,N-dimethylamino- Trans 3-(6- Yellowisn 2405- 4oxo-4Hl-benzopyra,n- N,N-dimethylfine 242.5 10 3-carboxaldehyde amino-4-oxoneedle [decomposi- 4H-l-benzo tion) Ef -3)- Malonic acid acrylic acid Methanol v 6-Ethyl-4-oxo-4H-L- Trans 3(6- Yellow 2245- benzopyra.n3 ethyl-4-oxoneedles 226 ll oarboxaldehyde 4H-lbenzo- (dec0mp0si pyran-3)- tion with acrylic acid Dimethylfoaming) Malonic acid formamide,

water 6-Methoxy-4-oXo-4Hl Trans 3-(6- Colorless 251-253 benzopyran-3- methoxylneedles (decomposil2 carboxaldehyde oxo-4H-l-- tion with benzopyran- Dimethyl foaming) mdcryllc for-.mamide,

ralonic acid acid water 6-Nitro-4oxo-4H-l- Trans 5-(6- Colorless 274-278 benzopyran-3 nitro-4-oxoneedlMMecomposil3 oarboxaldehyde 4H-l-benzotion with Miran-:3)- Keatone foammg) acrylic acid Malonic acid 6-Methyl-4-4-oXo-4Hl- Trans 3-(6- Pale 256 benzopyran-3- methyl-4- yellow (decomposi-w l4 carboxaldehyde oxo-4H-lneedles tion with benzopyranfoaming) 5)acrylic Malonic acid acid 232 9 Water Continued i Crystal Melting Example Starting compounds Product form point Solvent for I recrystal- 'lization v 6n-Butyl4-oXo-4H Trans 3-(6- White 211-212 1 j l-benzop 3 n-butyl-4- needles/ l5 carboxal ehyde oXo-4-H-l g; benzcpyran- ,l acrylic Methanol Malonic acid acid 6Chloro-4-oXo-4H- -l- Trans 3-(6- White 281-282 benzopyran-5- chloro-4- needley (decomposil6 carboxaldehyde oxo-4H-ltion w1th benzopyran- /bimethyl foaming) 3lsryllc formamide; Malonic acid acid a water,

* Purified by silica gel chromatography Solvent chloroform acetone formic acid (4:1:05)

Infrared absorption spectrum (KBr) (enf 5400,3 75w 1710((1001 1), l630,l620,l6OO

Mass spectrum: m/e 248(M EXAMPLE 17 A solution of 1,040 parts of 4 oxo-4H-1-benzopyran- 3-carboxaldehyde and 872 parts of monoethyl malonate in parts by volume of pyridine is heated in an oil bath at 110C for minutes. The solvent is removed to obtain the residue. Recrystallization from ethanol yields 210 parts of trans ethyl 3-(4-oxo-4H-lbenzopyran-3)acrylate as colorless long needles melting at 1 10 to 111C. Elemental analysis Calculated for C H O C, 68.84; H, 4.95 Found: C, 68.82; H, 4.87

EXAMPLE 18 A mixture of 1,740 parts of 4-oxo-4H-l-benzopyran- 3-carboxaldehyde and 1,550 parts monoamide in 10 parts by volume of pyridine is heated in an oil bath, temperature of which is at l 10C, for 1 hour. The reaction mixture is concentrated. The resulting residue is washed with water and collected by filtration. Recrystallization from parts by volume of acetone gives 790 parts of trans 3-(4-oxo-4H-l-benzopyran-3 )acrylamide as pale yellow prisms melting at 244 to 245C. Elemental analysis Calculated for C H NQ C, 66.97; H, 4.

2]; N, 6 Found: C, 66.30; H, 4.27; N; 6

A mixture of 690 parts of trans 3-(4-oxo-4H-lbenzopyran-3)acrylamide, 6 parts by volume of acetic acid and 6 parts by volume of 6N-sulfuric acid is refluxed for 36 hours. The reaction mixture is poured into ice-water and the resulting precipitates are collected by filtration and washed with water. Recrystallization from acetone gives 320 parts of trans 3-(4-oxo- 4H-l-benZopyran-3)acrylic acid as pale yellowish needles melting at 245"-246"((decomposition with foaming).

of malon- EXAMPLE 19 To a mixture of 10,440 parts of 4-oxo-4H-lbenzopyran-3-carb0xaldehyde and 5,400 parts of cyanoacetic acid is added 25 parts by volume of pyridine, dropwise, in an oil bath, at a temperature of l C, for 30 seconds and then the mixture is heated at l 10C for 8 minutes, after which time the reaction mixture is cooled. The precipitated crystals are collected by filtration and recrystallized three times from ethanol. The procedure yields 6,600 parts of trans 3-(4-oxo-4H-lbenzopyran-3)aerylonitrile as pale yellowish prisms melting at l92l94C. Elemental analysis Calculated for C, H NO C, 73.09; H, 3 3

Found: C, 73.48; H, N

EXAMPLE A solution of 204 parts of 7-methoxy-4-oxo-4H-lbenzopyran-3-carboxaldehyde and 130 parts of monomethyl malonate in 2 parts by volume of pyridine is heated in an oil bath at l l0C for 30 minutes. The solvent is removed to obtain the residue. Recrystallization from acetone yields 90 parts of trans methyl 3-(7- methoxy4-oxo-4H-l-benzopyran-3)acrylate as colorless needles melting at 164168C. Infrared absorption spectrum (KBr)(cm") l713,l660,1624,l600,1270,l240 Nuclear Magnetic Resonance spectrum(d -dimethylsulfoxidel blet,lH,J=l6Hz.), 3.93(singlet,3H),3.77(singlet,3H).

A mixture of 1.5 part by volume of glacial acetic acid, 1.5 parts by volume of concentrated hydrobromic acid and 260 parts of trans methyl 3-(7-methoxy-4- oxo-4H-l-benzopyran-3 )-acrylate is refluxed for about 2 hours. Then, the reaction mixture is poured into icewater and the resulting solids are collected by filtration and recrystallized from dimethylformamide-water. The procedure yields 110 parts of trans 3-(7-hydroxy-4- oxo-4H-l -benzopyran-3)acrylie acid as a lightyellowish solid melting at 288290C(decomposition with foaming).

By a procedure similar to that described above, yellow needles of trans 3-(6,7-dihydroxy-4-oxo-4H-lbenzopyran-3 )acrylic acid, melting at 300C or higher is obtained from trans 3-(6,7-diacetoxy-4-oxo4H-lhenzopyran3 )acrylic acid.

EXAMPLE 21 A mixture of 870 parts of4-oxo-4H-l-benzopyran-3- carboxaldehyde, 2 parts by volume of diethyl malonate and 4 parts by volume of acetic anhydride is refluxed for 1 hour. The solution is concentrated to dryness and the residual syrup is crystallized by cooling. The crystals are collected by filtration, washed with ethanol and recrystallized from ethanol, whereby 810 parts of ethyl 2-ethoxycarbonyl-3-(4-oxo-4H- l -ben2opyran- 3)acrylate is obtained as colorless plates melting at l08.5l09.5C. Infrared absorption spectrum (KBr)(cm") l725,l655,l635,l620,1275,1250,l220,760. Nuclear Magnetic Resonance spectrum (CDCl d:

H ),ca8.20( l H,doublet of doublet,.l=7 and 2l-lz.,chromone-H 7.76(1H,dou-

blet,

J=lHz.,H ),7.3-7.7(3H,multiplet,chromone-H -H,,)

about 4.4 (4H,OCH about 1.4(6H, -CH

A mixture of 316 parts of ethyl 2-ethoxycarbonyl-3- (4-oxo-4H-l-benzopyran-3 )acrylate, 2 parts by volume of acetic acid and 2 parts by volume of 6N-sulfuric acid is refluxed for 3 hours. Then, the reaction mixture is poured into ice-water and the resulting precipitates are collected by filtration and recrystallized from acetone. The procedure yields 40 parts of trans 3-(4-oxo-4H-lbenzopyran-3 )acrylic acid.

EXAMPLE 22 In 10 parts by volume of water is suspended 216 parts of trans 3-(4-oxo-4H-l-benZopyran-3)acrylic acid. Then, the suspension is adjusted to a pH of 67 by using an equimolar amount of an aqueous solution of sodium hydroxide with respect to the starting material to dissolve the starting material in water. The solution is concentrated to dryness and ethanol is added to the concentrate. The resulting precipitates are collected by filtration and washed with diethyl ether. The procedure yields sodium trans 3-(4-oxo-4H- l -benzopyran- 3)acrylate as a pale yellowish powder which is readily soluble in water. Infrared absorption l645,l620,l560,980

EXAMPLE 23 In 5 parts by volume olethanol, 244 parts of trans 3- (6-ethyl-4-oxo-4H-l-benzopyran-3)acrylic acid is suspended. Then, the suspension is adjusted to a pH of 7 by using one part by volume of lN-aqueous solution of sodium hydroxide to dissolve the starting material. The solution is concentrated to dryness and the residue is dissolved in 10 parts by volume of methanol. The solutiort is decolorized with activated carbon and concentrated to dryness. Then, the pink residue is washed with 10 parts by volume of diethyl ether and dried. The procedure yields sodium trans 3-(6-ethyl4-oxo-4H- l benzopyran-3)acrylate as a pink powder which is readily soluble in water.

Infrared spectrum (cnf) l650,l6l8,l560,980

EXAMPLE 24 To 5 parts by volume of ethanol is added 145 parts of trans 3-(4-oxo-4H-l-henzopyran-3 )acrylic acid, followed by the addition of parts of DL- methylephcdrine. The mixture is warmed to dissolve the starting material. The solution is concentrated to dryness and the residue is washed with 5 parts by volume of ether. The precipitates are collected by filtra' spectrum (cm):

tion and recrystallized from 1.2 part by volume of ethanol. The procedure yields 165 parts of the DL- methylcphedrine salt of trans 3-(4-oxo-4H-1-benzopyran-3)acrylic acid as colorless pillars melting at 149C.

Elemental analysis (alculatcd for CZHHHOSNI C, 69.85; H, (1.37; N, 3.54 Found: C, 69.67; H. 6.22; N, 3.29

By a procedure similar to that described above, the ethanolamine salt of trans 3-(4-oxo-4H-1-benzopyran- 3)acrylic acid (melting point 147C, as colorless needles when recrystallized from ethanol) is obtained.

EXAMPLE 25 A mixture of 174 parts of 4-oxo-4H-1-benzopyran-3- carboxaldehyde, 125 parts of malonic acid and 200 parts of 2-methylimidazole is heated in an oil bath at 120C for minutes. After cooling, water is added to the reaction mixture and the solution is extracted with parts by volume of ethyl acetate. The water layer is made acid with concentrated hydrochloric acid and the solid separatedout is collected by filtration. The solid is crystallized from acetone. The procedure yields 50 parts of trans 3-(4-oxo-4H-l-benzopyran-3)acrylic acid as pale yellowish needles melting at 245246C (decomposition with foaming).

EXAMPLE 26 EXAMPLE 27 Some examples of compositions in which the compounds of this invention are utilized in the treatment of allergic disease are as follows:

A.(Tablell l) trans 3-(6-ethyl-4-oxo-4Hl-benzopyran3) mg.

acrylic acid (2) lactose 35 mg. (3) corn starch 150 mg. (4) microcrystalline cellulose 30 mg. (5) magnesium stearate 5 mg. 240 mg, per tablet (1), (2), (3 two-thirds of the amount of (4) and half of (5) are throughly mixed, and then the mixture is granulated. The remaining one-third quantity of (4) and half of the amount of (5) are added to the granules and compressed into tablets. The tablets thus prepared can further be coated with a suitable coating agent, e.g. sugar.

B. (Capsule) (l) trans 3-(6-ethyl-4-oxo-4Hl-benzopyran-3)- 20 mg,

acrylic acid (2) lactose 102 mg. (3) microcrystalline cellulose mg. (4) magnesium stearate 8 mg. 200 mg. per capsule (2), (3) and half of the amount of (4) are throughly mixed, and then the mixture is granulated. The remaining half of (4) is added to the granules and the whole is filled into a gelatin capsule.

C. (Injection) (1) sodium 3-(6-ethyl-4-oxo-4H-l-benzopyran-3)- 10 mg.

acrylate (2) inositol mg. (3) benzyl alcohol 20 mg.

All ingredients are dissolved in water to make 2.0 ml. of a solution (pH 7.5) serving as an injectable.

What is claimed is: l. A compound of the formula:

6 li l I CH=CH'-COOH 0 wherein m is 0, l or 2 and each of R, is a member selected from the group consisting of halogen, hydroxy, nitro, amino, lower alkylamino, lower alkyl, lower alkoxy, alkanoyloxy and benzoyloxy and the pharmaceutically acceptable salts thereof.

2. A compound as claimed in claim 1, wherein the pharmaceutically acceptable salt is a member selected from the group consisting of an alkali metal salt, ammo nium salt and an organic amine compound selected from the group consisting of mono, dior triethanolamine, diethylamine, triethylamine, dimethylephedrine, l-B,5-dihydroxy phenol)-L-isopro pyl-aminoethanol, isoproterenol (3,4-dihydroxy-a- [(isopropylamino) methyl] benzyl alcohol), hetrazan (diethyl carbamazine), and dextromethorphan (d-3- methoxy-N-methylmorphinan).

3. A compound as claimed in claim 2, wherein the pharmaceutically acceptable salt is DL- methylephedrinc salt.

4. A compound as claimed in claim 1, wherein R, is a lower alkyl group having up to six carbon atoms.

5. A compound as claimed in claim 1, wherein R, is a lower alkoxy group having up to four carbon atoms.

6. A compound as claimed in claim 1, wherein R, is a lower alkanoyloxy group having up to seven carbon atoms.

7. A compound as claimed in claim 1, wherein R, is a lower alkylamino selected from the group consisting of mono-lower alkylamino and di-lower alkylamino, said lower alkyl group having up to four carbon atoms.

8. A compound as claimed in claim 1, wherein R, is a halogen atom selected from the group consisting of chlorine, bromine, iodine and fluorine.

9. A compound as claimed in claim 1, wherein R, is nitro.

10. A compound as claimed in claim 1, which is 3-(4- oxo-4H-1-benzopyran-3)acrylic acid.

11. A compound as claimed in claim 1, which is 3- R (6,7-diacetoxy-4-oxo-4H-1-benzopyran-3 )acrylic acid. 2

12. A compound as claimed in claim 1, which is 3-(5- CH hydroxy-4-oxo-4H-l-benzopyran-3)acrylic acid. 2

13. A compound as claimed in claim 1, which is 3-(7- 5 R3 hydroxy-4-oxo-4H- l -benzopyran-3 )acrylic acid.

14. A compound as claimed in claim 1, which is 3-(7- methoxy-4-oxo-4H-l -benzopyran-3)acrylie acid.

15. A compound as claimed in claim 1, which is 3-(6- methyl-4-oxo-4H- l -benzopyran-3 )acrylic acid.

16. A compound as claimed in claim 1, which is 3-(6- ethyl-4-oxo-4H-l-benzopyran-3 )acrylic acid.

wherein R and R which may be the same or different are each selected from the group consisting of cyano,

l0 carboxyl, and esterified carboxyl and earboxyamide and when R and R are said esterified carboxyl or carboxyamide, the resulting product is hydrolyzed.

21. A method as claimed in claim 20 wherein the A Compound as claimed in claim 1, which is pharmaceutically acceptable salt is an alkali metal salt. ypy y acidammonium salt or an organic amine salt selected from A Compound as claimed in claim which is the group consisting of mono, dior triethanolaminc, nitro-4-oxo-4H-l-benzopyran-3)acrylic acid. diethylamine, triethylamine, di-methylephedrine,

19. A compound as claimed in claim 1, which is 3-(6- (3,5-dihydroxy phenol)-L-isopropyl-aminoethanol, isonbutyl-4-oxo-4Hl-benzopyran-3)acrylie acid. proterenol (3,4-dihydroxya-benzyl alcohol), hetrazan 20. A method for producing a compound of the for- 20 (diethylcarbamazine), and dextromethorphan (d-3- mula: methoxy-N-methylmorphinan).

[ )m CH=CHCOOH] I T l CH=CH"COOH- wherein m is 0, l, or 2 and R is a member selected 22, A h d a claimed in claim 20, wherein R is from the group consisting of halogch, y y a lower alkyl group having up to six carbon atoms. amino, lower alkylamino, lower alkyl, lower alkoxy and 23 A th d l imed in claim 20, wherein R is lower alkanoyloxy and bchzylcxy which comprises a lower alkoxy group having up to four carbon atoms. acting 3 Chmphuhd of thc formula: 24. A method as claimed in claim 20, wherein R, is a lower alkanoyloxy group having up to seven carbon atoms.

25. A method as claimed in claim 20, wherein R is a lower alkylamino selected from the group consisting of mono-lower alkylamino and di-lower alkylamino, said lower alk l rou bein that havin u to four car- (Rlml 4O bon atoms. y g p g g p or an acid anhydride.

GHQ

wherein m and R are as defined above with a compound of the formula UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 I 872 I 108 Dated M h 8, 1975 Inventor(s) Nohara, et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Page 1, Under "United States Patent": Change 'Ukyo et al" to -Nohara et al-. I

Page 1, After "Inventors: Delete all the information and substitute therefor the following: -Akira Nohara, Kyoto;

Tomonobu Umetani, Osaka; Yoshibumi Miyata, Osaka; Yasushi Sanno, Osaka; all of Japan Column 8, line 42: After "thylsulfoxide) change "d" to Column 15, line 21: After "sulfoxide) change "d" to (P line 46: After "sulfoxide) add d:

line 47: Change "1.6GHz." to -l6Hz.-.

Column 16, line 12 Change "d" to S I of claim 20 Column 19, in the first formula Delete the brackets &

Column 20, Delete claim 21 in its entirety, and renumber the remaining claims 22-28 to read 21-27 respectively.

Signed and Scaled this sixteenth Day Of March 1976 [SEAL] Arrest:

RUTH. C. MASON C. MARSHALL DANN Arresting Officer (ummixsimzer ufPatents and Trademarks 

1. A COMPOUND OF THE FORMULA:
 2. A compound as claimed in claim 1, wherein the pharmaceutically acceptable salt is a member selected from the group consisting of an alkali metal salt, ammonium salt and an organic amine compound selected from the group consisting of mono, di- or triethanolamine, diethylamine, triethylamine, di-methylephedrine, 1- Beta ,5-dihydroxy phenol)-L-isopropyl-aminoethanol, isoproterenol (3,4-dihydroxy-a-((isopropylamino) methyl) benzyl alcohol), hetrazan (diethyl carbamazine), and dextromethorphan (d-3-methoxy-N-methylmorphinan).
 3. A compound as claimed in claim 2, wherein the pharmaceutically accEptable salt is DL-methylephedrine salt.
 4. A compound as claimed in claim 1, wherein R1 is a lower alkyl group having up to six carbon atoms.
 5. A compound as claimed in claim 1, wherein R1 is a lower alkoxy group having up to four carbon atoms.
 6. A compound as claimed in claim 1, wherein R1 is a lower alkanoyloxy group having up to seven carbon atoms.
 7. A compound as claimed in claim 1, wherein R1 is a lower alkylamino selected from the group consisting of mono-lower alkylamino and di-lower alkylamino, said lower alkyl group having up to four carbon atoms.
 8. A compound as claimed in claim 1, wherein R1 is a halogen atom selected from the group consisting of chlorine, bromine, iodine and fluorine.
 9. A compound as claimed in claim 1, wherein R1 is nitro.
 10. A compound as claimed in claim 1, which is 3-(4-oxo-4H-1-benzopyran-3)acrylic acid.
 11. A compound as claimed in claim 1, which is 3-(6,7-diacetoxy-4-oxo-4H-1-benzopyran-3)acrylic acid.
 12. A compound as claimed in claim 1, which is 3-(5-hydroxy-4-oxo-4H-1-benzopyran-3)acrylic acid.
 13. A compound as claimed in claim 1, which is 3-(7-hydroxy-4-oxo-4H-1-benzopyran-3)acrylic acid.
 14. A compound as claimed in claim 1, which is 3-(7-methoxy-4-oxo-4H-1-benzopyran-3)acrylic acid.
 15. A compound as claimed in claim 1, which is 3-(6-methyl-4-oxo-4H-1-benzopyran-3)acrylic acid.
 16. A compound as claimed in claim 1, which is 3-(6-ethyl-4-oxo-4H-1-benzopyran-3)acrylic acid.
 17. A compound as claimed in claim 1, which is 3-(6-methoxy-4-oxo-4H-1-benzopyran-3)acrylic acid.
 18. A compound as claimed in claim 1, which is 3-(6-nitro-4-oxo-4H-1-benzopyran-3)acrylic acid.
 19. A compound as claimed in claim 1, which is 3-(6-n-butyl-4-oxo-4H-1-benzopyran-3)acrylic acid.
 20. A method for producing a compound of the formula:
 21. A method as claimed in claim 20 wherein the pharmaceutically acceptable salt is an alkali metal salt, ammonium salt or an organic amine salt selected from the group consisting of mono, di- or triethanolamine, diethylamine, triethylamine, di-methylephedrine, 1-(3,5-dihydroxy phenol)-L-isopropyl-aminoethanol, isoproterenol (3,4-dihydroxy- Alpha -benzyl alcohol), hetrazan (diethylcarbamazine), and dextromethorphan (d-3-methoxy-N-methylmorphinan).
 22. A method as claimed in claim 20, wherein R1 is a lower alkyl group having up to six carbon atoms.
 23. A method as claimed in claim 20, wherein R1 is a lower alkoxy group having up to four carbon atoms.
 24. A method as claimed in claim 20, wherein R1 is a lower alkanoyloxy group having up to seven carbon atoms.
 25. A method as claimed in claim 20, wherein R1 is a lower alkylamino selected from the group consisting of mono-lower alkylamino and di-lower alkylamino, said lower alkyl group being that having up to four carbon atoms.
 26. A method as claimed in claim 20, wherein R1 is a halogen atom selected from the group consisting of chlorine, bromine, iodine and fluorine.
 27. A method as claimed in claim 20, wherein R1 is nitro.
 28. A method as claimed in claim 20, wherein the reaction is conducted in the presence of a basic reagent or an acid anhydride. 